CN109265451B - Butyrylcholinesterase selective inhibitor and preparation method and application thereof - Google Patents
Butyrylcholinesterase selective inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a butyrylcholinesterase selective inhibitor, a preparation method and application thereof. The invention discloses a compound shown as a formula (I) and also discloses application of the compound in preparing a medicament for preventing or treating Alzheimer's disease. The inventor evaluates that the compound shown in the formula (I) treats Alzheimer disease (especially moderate and severe Alzheimer disease) by taking butyrylcholinesterase inhibitory activity, selective screening and Morris water maze experiments as carriers, finds that the compound has good in vitro and in vivo activity and extremely high selectivity, and can be used as a precursor substance for further developing the effect of developing Alzheimer disease by selectively inhibiting butyrylcholinesterase.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a butyrylcholinesterase selective inhibitor, and a preparation method and application thereof.
Background
Alzheimer's Disease (AD) is a systemic neurodegenerative syndrome of the brain, with clinical manifestations of central cognitive decline, mental and motor disorders, etc. Currently, AD has become a global problem with aging population, and has become a great threat to the health of the elderly as well as to the overall medical resources of society. According to the 2016 world Alzheimer's disease report statistics, the number of worldwide AD patients reaches 4680 million people in 2015, and reaches 1.32 hundred million by 2050. Over the past five years, the worldwide capital investment in AD therapy has increased by over 35%, reaching 8180 billion dollars in 2015, and trillion dollars in 2018. The string of striking numbers clearly reveals the severe situation of preventing and treating AD, and the effective way to deal with the AD is very urgent and inexhaustible. Therefore, the discovery of effective AD prevention and treatment drugs has important basic research and clinical application values.
The pathological causes of AD are very complex, and no clear pathogenic factors have been found so far, and the pathological process involves multiple systems and links such as nerves, immunity, and blood circulation. Numerous studies have shown that the occurrence and development of AD are closely related to several factors: 1) pathological changes and dysfunction of the cholinergic system; 2) beta-amyloid protein (beta-amyloid, Abeta) tangles and deposits for inducing neuronal apoptosis; 3) tau protein is over-phosphorylated, forming Senile Plaque (SP), neurofibrillary tangles (NFT), which in turn leads to neuronal loss in the brain; 4) inflammatory reaction causing the change of the internal environment of brain body fluid and the rise of the level of active oxygen free radicals; 5) disorders of immune regulation in the brain. However, no clear causal relationship between AD and AD has been elucidated at present in any theory, which directly hinders the development of anti-AD drugs.
Although a number of potential strategies for treating AD have been proposed, they are in the basic research phase. The clinically effective drugs at present are cholinesterase inhibitors (donepezil, galantamine and rivastigmine) except that memantine is an N-methyl-D-aspartic acid receptor (NMDAR) blocker. The marketed drugs are only suitable for symptomatic treatment of mild and moderate AD, and the drugs effective for severe AD are seriously deficient. At present, the only effective drug for treating severe AD is memantine, but the effect is not satisfactory. The course of AD is lengthy and many patients with severe AD are still in a situation where no drugs are available.
Cholinesterase inhibitors designed based on the central cholinergic hypothesis remain the clinical first-choice strategy for the treatment of AD. This hypothesis suggests that severely damaged cholinergic neurons in the brain of AD patients, especially in the cortical and hippocampal, anterior Meynert basal ganglia and septal regions, lead to abnormally reduced levels of acetylcholine (ACh), which is closely associated with the pathological features of AD, especially cognitive dysfunction. The cholinesterase which is responsible for hydrolyzing ACh is a key factor for controlling the ACh level, so the excitability of the central cholinergic system can be improved and the learning and memory abilities of the old can be improved by inhibiting the activity of the cholinesterase, thereby playing a role in delaying the disease course of AD. Cholinesterase has two main members: acetylcholinesterase (Acetylcholinesterase, AChE) and Butyrylcholinesterase (Butyrcholinesterase, BuChE). Most studies currently available suggest that AChE can specifically recognize and hydrolyze ACh, a key target of its metabolism, and thus existing drugs are also mainly directed to AChE, such as donepezil and galantamine, which are both selective AChE inhibitors. For BuChE, since it is not the main metabolic node of ACh under normal conditions, it is often considered as a possible redundant mechanism of AChE formed by the body during natural evolution. However, in AD pathology, due to the severe choline neuron damage, AChE levels drop by 90% relative to normal and function is almost lost, while BuChE levels and function increase to 105-165% of normal, replacing AChE as the main metabolic enzyme for hydrolyzing ACh. Thus, for the treatment of severe AD, the key is not AChE, but BuChE. Although central targeting of drugs is a great concern for anti-AD drugs, complete tissue selectivity is still difficult to achieve, and therefore, selective AChE inhibitors or non-selective cholinesterase inhibitors have peripheral cholinergic side effects. However, multiple studies show that the growth and development of the BuChE knock-out mice are normal, no matter the center or the periphery of the BuChE knock-out mice is abnormal, the biological effect intensity of the BuChE knock-out mice is far lower than that of AChE, so that the BuChE knock-out mice can conclude that the BuChE knock-out mice have obviously lower cholinergic side effects caused by the selective BuChE inhibitor and have advantages in the aspect of the drug safety of AD treatment.
In conclusion, the specificity inhibition of BuChE has strong rationality and important research and application values for treating AD. However, most of the existing BuChE inhibitors appear along with the appearance of AChE inhibitors, and have the defects of small quantity, lack of structural novelty and diversity, poor selectivity and the like. Therefore, the development of the high-selectivity BuChE inhibitor with a brand-new framework has important significance and value.
Disclosure of Invention
The invention discloses a compound with anti-Alzheimer disease function, which is shown as a formula (I).
The structural formula of the invention is as follows:
wherein n is an integer of 1 to 4; r represents
Or R2Substituted naphthyl or quinoline;
wherein R is1Represents optionally substituted hydroxy, halogen, C1～C4Alkyl, halogen substituted C1～C4Alkyl radical, C1～C4Alkoxy radical, C1～C4Alkoxycarbonyl, C1～C4Acyl, phenyl, and,-O(CH2)mO-, cyano, nitro or-NR3R4Wherein m is 1 or 2, R3、R4Each independently represents hydrogen or C1～C3An alkyl group;
R2represents hydrogen, or optionally substituted C1～C4An alkyl group.
A compound having anti-Alzheimer's disease activity represented by the formula (I) or a pharmaceutically acceptable salt thereof, preferably n is 1 or 2, R represents
Or R2Substituted naphthyl or quinoline, R1Selected from optionally substituted fluoro, chloro, bromo, methyl, isopropyl, methoxy, methoxycarbonyl, acetyl, phenyl, -OCH 2O-, cyano, nitro or-NR3R4，R3、R4Independently selected from hydrogen or methyl; r is2Selected from hydrogen or methyl.
A compound having anti-alzheimer's disease represented by the formula (I) or a pharmaceutically acceptable salt thereof, further preferably n ═ is 1 or 2; r is selected from nitro, phenyl which is mono-substituted or polysubstituted by methyl, naphthyl which is unsubstituted or substituted by methyl or quinoline.
The compound having anti-alzheimer's disease represented by the formula (I) is further preferably any of the following compounds:
the pharmaceutically acceptable salt is selected from hydrochloride, maleate and citrate; the pharmaceutically acceptable salt of the compound shown in the formula (I) has the same or better pharmacodynamic activity as the compound shown in the formula (I).
A process for preparing a compound having anti-alzheimer's disease activity according to formula (I) comprising: 2-cyanomethyl benzimidazole is used as an initial raw material, and the 4- (1H-benzo [ d ] is obtained by two-step reaction of sodium nitrite (1-1.2 times equivalent) and hydroxylamine hydrochloride (2-4 times equivalent)]Imidazol-2-yl) -1,2, 5-oxadiazol-3-amine
Reacting arylamine with different ring systems and different substitutions with chloroacetyl chloride, 3-chloropropionyl chloride, 4-chlorobutyryl chloride or 5-chlorovaleryl chloride (1.3-2 times equivalent) respectively to form corresponding amide intermediates 
Then 4- (1H-benzo [ d ]]Imidazol-2-yl) -1,2, 5-oxadiazol-3-amine
(1: 0.8-1.2 equivalent) to obtain the selective butyrylcholinesterase inhibitor shown in formula (I) and capable of resisting Alzheimer's disease. The reaction formula is as follows:
wherein n is an integer of 1-4; r represents
Or R2Substituted naphthyl or quinoline;
wherein R is1Represents optionally substituted hydroxy, halogen, C1～C4Alkyl, halogen substituted C1～C4Alkyl radical, C1～C4Alkoxy radical, C1～C4Alkoxycarbonyl, C1～C4Acyl, phenyl, -O (CH)2)mO-, cyano, nitro or-NR3R4Wherein m is 1 or 2, R3、R4Each independently represents hydrogen or C1～C3An alkyl group;
R2represents hydrogen, or optionally substituted C1～C4An alkyl group.
The invention comprises the application of the compound in preparing a medicament for preventing or treating Alzheimer's disease.
The compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, powder, syrup, liquid, suspending agents and injection, and common medicinal auxiliary materials such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.
The clinical administration mode of the compound of the invention can adopt oral administration, injection and other modes.
The clinical dosage of the compound of the invention is 0.01 mg-1000 mg/day, and the dosage can deviate from the range according to the severity of the disease condition or different dosage forms.
A pharmaceutical composition comprises the compound shown in the formula (I) of the invention.
Has the advantages that:
the invention provides a series of compounds shown in a formula (I), and the compounds shown in the formula (I) are evaluated by taking butyrylcholinesterase inhibition activity, selective screening and a Morris water maze experiment as carriers to treat the curative effect of the compounds shown in the formula (I) on Alzheimer disease (especially moderate and severe Alzheimer disease), have good in vitro and in vivo activity and extremely high selectivity, and can be used as precursor substances for further developing the effect of developing Alzheimer disease by selectively inhibiting butyrylcholinesterase.
Drawings
FIG. 1 time to plateau for mice
FIG. 2 trajectory of mouse arrival at the plateau (A: control group; B: model group; C: tacrine group; D: Compound 1-treated group; E: Compound 5-treated group; F: Compound 6-treated group; G: Compound 7-treated group)
Detailed Description
Example 1
(1) Synthesis of 4- (1H-benzo [ d ] imidazol-2-yl) -1,2, 5-oxadiazol-3-amine (intermediate 1)
2-cyanomethylbenzimidazole (1g,6.36mmol) is taken out and dissolved in an eggplant-shaped bottle by acetic acid (10ml), an aqueous solution of sodium nitrite (0.44g,6.36mmol) is dropwise added under ice bath, solid is generated, the mixture is stirred in the ice bath for 40 minutes and then is filtered, and a filter cake is washed once by water and twice by diethyl ether. Taking another eggplant-shaped bottle, adding hydroxylamine hydrochloride (0.53g,7.63mmol) into ice bath, adding water as a solvent, Adding potassium hydroxide (0.54g,9.54mmol), then adding diglyme (6ml), finally adding the filter cake in the previous step, heating the reaction system to room temperature, refluxing for 6 hours, and cooling to room temperature; a large amount of gold pink crystals are separated out, filtered, the filter cake is washed once by water and twice by ether, and dried to obtain an intermediate 4- (1H-benzo [ d ]]Imidazol-2-yl) -1,2, 5-oxadiazol-3-amine (1.01g, 78.90% yield).1H NMR(300MHz,DMSO-d6):δ13.66(s,1H,NH),7.68(s,2H,NH2),7.32(q,J＝3.09Hz,2H,ArH),6.81(s,2H,ArH).MS(ESI):calcd.for C9H8N5O[M+H]+202.0723found 202.0720.
(2) Synthesis of 2-chloro-N- (2-methylquinolin-6-yl) acetamide (intermediate 2)
2-methyl-6-aminoquinoline (200mg,1.26mmol) was taken and dissolved in chloroform (5ml), and sodium hydrogencarbonate (127.44mg,1.52mmol) was added thereto, and after stirring at room temperature for 15 minutes, a chloroform solution of chloroacetyl chloride (214.16mg,1.90mmol) was slowly dropped into the reaction flask, and the mixture was stirred at room temperature for 4 hours. Water was added for extraction, the combined organic phases were collected, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 2-chloro-N- (2-methylquinolin-6-yl) acetamide as a white solid (243.89mg, yield 82.21%).1H NMR(300MHz,DMSO-d6):δ11.30(s,1H,NHCO),9.00(s,1H,ArH),8.70(s,1H,ArH),8.39(s,1H,ArH),8.15(s,1H,ArH),7.90(s,1H,ArH),4.42(s,2H,CH 2),2.93(s,3H,CH 3).MS(ESI):MS(ESI):calcd.for C12H12ClN2O[M+H]+235.0905found235.0638.
Note: the 2-methyl-6-aminoquinoline is prepared by self-preparation, and the method comprises the following steps: putting paranitroaniline (500mg,3.65mmol) in an eggplant-shaped bottle, dropwise adding paraldehyde (1.45g,10.94mmol) into the reaction bottle by using concentrated hydrochloric acid as a solvent, heating the reaction solution for refluxing for 6 hours after dropping, and cooling to room temperature; the reaction solution was adjusted to pH 8 with potassium hydroxide, extracted with dichloromethane several times, the organic phases were combined, washed with saturated brine once, the organic phase was dried, and separated by silica gel column chromatography to give 2-methyl-6-nitroquinoline as an intermediate (460mg, 67.40% yield). Wherein, the eluant of the silica gel column chromatography is dichloromethane. 1H NMR(300MHz,DMSO-d6):δ8.99(d,J＝2.46Hz,1H,ArH)，8.57(d,J＝8.46Hz,1H,ArH),8.41(dd,J＝9.21,2.58Hz,1H,ArH),8.09(d,J＝9.24Hz,1H,ArH),7.62(d,J＝8.49Hz,1H,ArH),2.72(s,3H,CH 3).MS(ESI):calcd.for C10H9N2O2[M+H]+190.0692found 190.0690.
The 2-methyl-6-nitroquinoline (500mg,2.66mmol) is taken to be put in an eggplant-shaped bottle, ethanol is added for dissolution, hydrochloric acid (20ml) with the concentration of 9M is dripped into the reaction bottle, and then ethanol solution of stannous chloride (2.02g,10.63mmol) is dripped dropwise. After the dripping is finished, heating and refluxing the reaction solution for 5 hours, and cooling to room temperature; the ethanol was removed, the remaining solution was adjusted to pH 9 with sodium hydroxide solid in ice bath, the milky white emulsion was extracted five times with ethyl acetate, the organic phases were combined, celite was added and stirred overnight, suction filtered the next day, and the filtrate was spin dried to give a white solid, intermediate 2-methyl-6-aminoquinoline (363.29mg, 86.43%).1H NMR(300MHz,DMSO-d6):δ7.83(d,J＝8.43Hz,1H,ArH),7.61(d,J＝8.91Hz,1H,ArH),7.16(q,J＝8.40Hz,2H,ArH),6.77(d,J＝1.98Hz,1H,ArH),5.44(s,2H,NH 2),2.53(s,3H,CH 3).MS(ESI):calcd.for C10H9N2O2[M+H]+160.0950found 159.0922.
(3) Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (2-methylquinolin-6-yl) acetamide
Placing 2-chloro-N- (2-methylquinolin-6-yl) acetamide (intermediate 2,194.41mg,0.83mmol) in a eggplant-shaped bottle, adding DMF (6ml) to dissolve, and adding cesium carbonate (269.91mg,0.83mmol) and 4- (1H-benzo [ d ] sequentially]Imidazole-2-yl) -1,2, 5-oxadiazole-3-amine (intermediate 1,150mg,0.75mmol) reacts for 9 hours at 70 ℃, water is added to separate out a large amount of solid, the solid is filtered, washed twice with ethyl acetate and twice with methanol, and a filter cake is dried to obtain white solid, namely 2- (2- (4-amino-1, 2, 5-oxadiazole-3-yl) -1H-benzo [ d ] ]Imidazol-1-yl) -N- (2-methylquinolin-6-yl) acetamide (compound 1,230mg, 77.24% yield). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.88(s,1H,NHCO),8.26(s,1H,ArH),8.11(d,J＝8.40Hz,1H,ArH),7.88(t,J＝6.69Hz,3H,ArH,NH 2),7.76(d,J＝9.18Hz,1H,ArH),7.34-7.48(m,3H,ArH),7.05(s,2H,ArH),5.67(s,2H,CH 2),2.62(s,3H,CH 3).MS(ESI):calcd.for C21H17N7O2[M+H+]400.1520found 400.1522.
Example 2
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (quinolin-6-yl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (quinolin-6-yl) acetamide to give a milky white solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] c]Imidazol-1-yl) -N- (quinolin-6-yl) acetamide (compound 2). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.95(s,1H NHCO),8.80(s,1H,ArH),8.33(s,1H,ArH),8.24(d,J＝8.34Hz,1H,ArH),8.02(d,J＝9.39Hz,1H,ArH),7.91-7.81(m,3H,ArH,NH 2)7.49-7.38(m,3H,ArH),7.05(s,2H,ArH),5.69(s,2H,CH 2).MS(ESI):calcd.for C20H15N7O2[M+H+]386.1365found 386.1359.
Example 3
Synthesis of 3- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (quinolin-6-yl) propionamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 3-chloro-N- (quinolin-6-yl) propanamide to give a milky white solid compound, i.e., 3- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d [ -d]Imidazol-1-yl) -N- (quinolin-6-yl) propionamide (compound 3). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.40(s,1H,NHCO),8.76(dd,J＝1.56,4.14Hz,1H,ArH),8.21-8.25(m,2H,ArH),7.91(d,J＝9.06Hz,1H,ArH),7.65(d,J＝8.13Hz,1H,ArH),7.81(d,J＝7.89Hz,1H,ArH)7.65(dd,J＝2.28,9.06Hz,1H,ArH),7.47(q,J＝3.54Hz,1H,ArH),7.40(d,J＝7.26Hz,1H,ArH)7.32(t,J＝7.38Hz,1H,ArH),7.01(s,2H,NH 2),5.02(t,J＝6.66Hz,2H,CH 2Cl),3.03(t,J＝6.54Hz,2H,CH 2CO).HR-MS(ESI):calcd.for C21H17N7O2[M+H+]400.1522found 400.1523.
Example 4
Synthesis of 5- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (quinolin-6-yl) pentanamide:
With reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 5-chloro-N- (quinolin-6-yl) pentanamide to give a pale yellow solid compound, i.e., 5- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ], (I)]Imidazol-1-yl) -N- (quinolin-6-yl) pentanamide. TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.36(s,1H,NHCO),8.76(d,J＝3.99Hz,1H,ArH),8.37(s,1H,ArH),8.25(d,J＝8.52Hz,1H,ArH),7.94(d,J＝8.79Hz,1H,ArH),7.84(d,J＝8.31Hz,2H,ArH),7.77(d,J＝9.09Hz,1H,ArH),7.48-7.34(m,3H,ArH,NH 2),7.04(s,2H,ArH),4.73(t,J＝7.05Hz,2H,CH 2N),2.45(t,J＝6.78Hz,2H,CH 2CONH),1.94-1.85(m,2H,CH 2CH2N),1.74-1.65(m,2H,CH 2CH 2CONH).MS(ESI):calcd.for C23H21N7O2[M+H+]428.1835found428.1836.
Example 5
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (quinolin-5-yl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (quinolin-5-yl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] c]Imidazol-1-yl) -N- (quinolin-5-yl) acetamide (compound 4). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.68(s,1H,NHCO),8.95(s,1H,ArH),8.63(d,J＝8.25Hz,1H,ArH),7.90(d,J＝6.51Hz,1H,ArH),7.75(d,J＝7.26Hz,1H,ArH),7.71(s,2H,NH 2),7.63(q,J＝4.29Hz,1H,ArH),7.48(t,J＝7.35Hz,1H,ArH),7.40(t,J＝7.32Hz,1H,ArH),7.03(s,2H,ArH),5.78(s,2H,CH 2).MS(ESI):calcd.for C20H15N7O2[M+H+]386.1360found 386.1297.
Example 6
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (quinolin-4-yl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (quinolin-4-yl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d [ -d ] N-methyl-ethyl ] -phenyl ]Imidazol-1-yl) -N- (quinolin-4-yl) acetamide (compound 5). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.92(s,1H,NHCO),8.97(d,J＝8.03Hz,1H,ArH),8.64(d,J＝8.25Hz,1H,ArH),7.97(d,J＝7.91Hz,1H,ArH),7.91-7.83(m,3H,ArH,NH 2),7.65(t,J＝7.25Hz,1H,ArH),7.55(t,J＝7.05Hz,1H,ArH),7.49-7.38(m,2H,ArH),7.05(s,2H,ArH),5.73(s,2H,CH 2).MS(ESI):calcd.for C20H15N7O2[M+H+]386.1360found 386.1287.
Example 7
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (quinolin-3-yl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (quinolin-3-yl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] (I)]Imidazol-1-yl) -N- (quinolin-3-yl) acetamide (compound 6). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ11.12(s,1H,NHCO),8.97(d,J＝2.43Hz,1H,ArH),8.64(d,J＝2.19Hz,1H,ArH),7.93(d,J＝8.28Hz,1H,ArH),7.91-7.86(m,3H,ArH,NH 2),7.65(t,J＝6.90Hz,1H,ArH),7.58(t,J＝7.05Hz,1H,ArH),7.49-7.38(m,2H,ArH),7.04(s,2H,ArH),5.71(s,2H,CH 2).MS(ESI):calcd.for C20H15N7O2[M+H+]386.1360found 386.1358.
Example 8
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (naphthalen-1-yl) acetamide:
referring to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (naphthalen-1-yl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] N]Imidazol-1-yl) -N- (naphthalen-1-yl) acetamide (compound 7). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.47(s,1H,NHCO),8.23(d,J＝7.59Hz,1H,ArH),7.86(m,3H,ArH),7.79(d,J＝7.92Hz,1H,ArH),7.54-7.65(m,3H,ArH),7.48(t,J＝7.68Hz,2H,ArH),7.40(t,J＝7.92Hz,2H,ArH)6.99(s,2H,NH 2),5.78(s,2H,CH 2Cl).HR-MS(ESI):calcd.for C21H16N6O2[M+H+]385.1413found 385.1409.
Example 9
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (naphthalen-2-yl) acetamide:
Referring to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (naphthalen-2-yl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] N]Imidazol-1-yl) -N- (naphthalen-2-yl) acetamide. TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.81(s,1H,NHCO),8.25(d,J＝1.65Hz,1H,ArH),7.91-7.83(m,4H,ArH,NH 2),7.77(d,J＝7.83Hz,ArH),7.61(dd,J＝2.07 8.85Hz,1H,ArH),7.48-7.38(m,4H,ArH),7.05(s,2H,ArH),5.67(s,2H,CH 2Cl).
Example 10
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N-phenylacetamide:
referring to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N-phenylacetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d]Imidazol-1-yl) -N-phenylacetamide (compound 8). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.51(s,1H NHCO),7.88(d,J＝7.83Hz,1H,ArH),7.81(d,J＝7.89Hz,1H,ArH),7.85(s,1H,ArH),7.55(s,1H,ArH),7.39-7.47(m,2H,ArH),7.32(t,J＝7.68Hz,2H,ArH),7.07(t,J＝7.29Hz,1H,ArH),6.98(s,2H,NH 2),6.81(s,1H,ArH),5.69(s,2H,CH 2).HR-MS(ESI):calcd.for C17H14N6O2[M+H+]335.1521found 334.1245.
Example 11
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (2-chlorophenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (2-chlorophenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] acetamide]Imidazol-1-yl) -N- (2-chlorophenyl) acetamide (compound 9). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm. 1H NMR(300MHz,DMSO-d6):δ10.09(s,1H,NHCO),7.84(dd,J＝7.53,16.88Hz,2H,ArH),7.67(d,J＝8.03Hz,1H,ArH),7.36-7.53(m,3H,ArH,NH 2),7.31(t,J＝7.55Hz,1H,ArH),7.20(t,J＝7.68Hz,1H,ArH),6.96(s,2H,ArH),5.68(s,2H,CH 2Cl).HR-MS(ESI):calcd.for C17H13ClN6O2[M+H+]369.0867found 369.0862.
Example 12
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (3-fluorophenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (3-fluorophenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] c]Imidazol-1-yl) -N- (3-fluorophenyl) acetamide (compound 10). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.99(s,1H,NHCO),7.86(dd,J＝7.29,12.51Hz,2H,ArH),7.54(d,J＝11.4Hz,1H,ArH),7.34-7.47(m,4H,ArH,NH 2),7.02(s,2H,ArH),6.87-6.94(m,1H,ArH),5.62(s,2H,CH 2Cl).HR-MS(ESI):calcd.for C18H16N6O2[M+H+]353.1162found 353.1171.
Example 13
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (3-methylphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (3-methylphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] ne]Imidazol-1-yl) -N- (3-methylphenyl) acetamide (compound 11). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.49(s,1H,NHCO),7.85(dd,J＝7.23,17.22Hz,2H,ArH),7.33-7.47(m,4H,ArH,NH 2),7.17-7.22(t,J＝7.68Hz,1H,ArH),7.02(s,2H,ArH),6.89(d,J＝7.53Hz,1H,ArH),5.58(s,2H,CH 2Cl),2.26(s,3H,CH 3).HR-MS(ESI):calcd.for C18H16N6O2[M+H+]349.1383found 349.1413.
Example 14
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (3-methoxyphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (3,4, 5-trimethoxyphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] b ]Imidazol-1-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide (compound 12).1H NMR(300MHz,DMSO-d6):δ10.57(s,1H,NHCO),7.85(dd,J＝7.41,15.02Hz,2H,ArH),7.48-7.36(m,2H,ArH),7.29(t,J＝2.13Hz,1H,ArH),7.23(t,J＝8.13Hz,1H,ArH),7.11(d,J＝8.07Hz,1H,ArH),7.03(s,2H,ArH),6.65(dd,J＝2.34,7.92Hz,1H,ArH),5.59(s,2H,CH 2Cl).
Example 15
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-chlorophenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-chlorophenyl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] c]Imidazol-1-yl) -N- (4-chlorophenyl) acetamide (compound 13). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.71(s,1H,NHCO),7.86(dd,J＝8.13,11.36Hz,2H,ArH),7.57-7.36(m,4H,ArH,NH 2),7.02(s,2H,ArH),5.59(s,2H,CH 2Cl).HR-MS(ESI):calcd.for C17H13ClN6O2[M+H+]369.0867found 369.0866.
Example 16
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-bromophenyl) acetamide:
referring to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-bromophenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d [ -d]Imidazol-1-yl) -N- (4-bromophenyl) acetamide (compound 14). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.70(s,1H,NHCO),7.85(dd,J＝7.59,13.50Hz,2H,ArH),7.60(d,J＝8.85Hz,2H,ArH),7.45-7.36(m,4H,ArH,NH 2),7.01(s,2H,ArH),5.59(s,2H,CH 2Cl).HR-MS(ESI):calcd.for C17H13BrN6O2[M+H+]415.0341found 415.0338.
Example 17
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-methylphenyl) acetamide:
With reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-methylphenyl) acetamide to obtain a pale yellow solid compound, namely 2- (2- (4-amino-1, 2, 5-oxadiazole) -acetic acid3-yl) -1H-benzo [ d]Imidazol-1-yl) -N- (4-methylphenyl) acetamide (compound 15). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.46(s,1H,NHCO),7.85(dd,J＝7.44,15.95Hz,2H,ArH),7.36-7.47(m,4H,ArH,NH 2),7.12(d,J＝8.34Hz,2H,ArH),7.02(s,2H,ArH),5.57(s,2H,CH 2Cl),2.25(s,3H,CH 3).HR-MS(ESI):calcd.for C18H17N5O2[M+H+]349.1408found 349.1397.
Example 18
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-methoxyphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-methoxyphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] c]Imidazol-1-yl) -N- (4-methoxyphenyl) acetamide (compound 16). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.41(s,1H,NHCO),7.84(dd,J＝7.26,16.38Hz,2H,ArH),7.48(d,J＝9.09Hz,ArH),7.03(s,2H,NH 2),6.89(d,J＝9.09Hz,2H,ArH),5.56(s,2H,CH 2Cl),3.72(s,3H,OCH 3).HR-MS(ESI):calcd.for C18H16N6O3[M+H+]365.1362found 365.1357.
Example 19
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-acetylphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-acetylphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d [ -d ] N- (4-aminophenyl) acetamide ]Imidazol-1-yl) -N- (4-acetylphenyl) acetamide (compound 17). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.87(s,1H,NHCO),7.94(d,J＝8.76Hz,2H,ArH),7.86(dd,J＝7.44,14.81Hz,2H,ArH),7.71(d,J＝8.79Hz,2H,ArH),7.37-7.48(m,2H,ArH),7.01(s,2H,NH 2),5.63(s,2H,CH 2Cl),2.53(s,3H,CH 3).HR-MS(ESI):calcd.for C19H12N6O3[M+H+]377.1362found 377.1356.
Example 20
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-methoxycarbonylphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-acetylphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] c]Imidazol-1-yl) -N- (4-acetylphenyl) acetamide (compound 18). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.87(s,1H,NHCO),7.93(d,J＝8.79Hz,2H,ArH),7.85(dd,J＝7.53,15.90Hz,2H,ArH),7.71(d,J＝8.88Hz,2H,ArH),7.36-7.48(m,2H,ArH),6.98(s,2H,NH 2),5.63(s,2H,CH 2Cl),3.83(s,3H,CH 3).HR-MS(ESI):calcd.for C19H16N6O4[M+H+]393.1311found 393.1307.
Example 21
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-nitrophenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-nitrophenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] c]Imidazol-1-yl) -N- (4-nitrophenyl) acetamide (compound 19). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ11.20(s,1H,NHCO),8.24(d,J＝9.27Hz,2H,ArH),7.81-7.90(m,4H,ArH,NH 2),7.37-7.48(m,2H,ArH),7.01(s,2H,ArH),5.66(s,2H,CH 2Cl).HR-MS(ESI):calcd.for C17H13N7O4[M+H+]380.1107found 380.1108.
Example 22
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-aminophenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-aminophenyl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] ne]Imidazol-1-yl) -N- (4-nitrophenyl) acetamide (compound 20). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.48(s,1H,NHCO),7.85(d,J＝7.05Hz,1H,ArH),7.87(d,J＝7.77Hz,1H,ArH),7.37-7.43(m,3H,ArH,NH 2),7.18(d,J＝5.79Hz,2H,ArH),6.94(s,2H,ArH),6.50(d,J＝5.82Hz,1H,ArH)5.51(s,2H,CH 2Cl),4.81(s,2H,NH 2).HR-MS(ESI):calcd.for C18H16N6O2[M+H+]350.1365found 350.1349.
Example 23
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-isopropylphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-isopropylphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] ne]Imidazol-1-yl) -N- (4-isopropylphenyl) acetamide. TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.47(s,1H,NHCO),7.84(dd,J＝7.53,17.40Hz,2H,ArH),7.38-7.49(m,4H,ArH,NH 2),7.19(s,1H,ArH),7.16(s,1H,ArH),7.02(s,2H,ArH),5.57(s,2H,CH 2Cl),2.79-2.88(m,1H,CH),1.18(s,3H,CH 3),1.16(s,3H,CH 3).HR-MS(ESI):calcd.for C18H16N6O2[M+H+]377.2726found 377.1703.
Example 24
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-acetamidophenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-acetamidophenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d [ -d ] N-acetyl-l-methyl-ethyl ] -phenyl-ethyl acetate ]Imidazol-1-yl) -N- (4-acetamidophenyl) acetamide (compound 21). TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.48(s,1H,NHCOCH2),9.89(s,1H,NHCOCH3),7.81-7.88(m,2H,ArH),7.38-7.49(m,6H,ArH,NH 2),7.02(s,2H,ArH),5.57(s,2H,CH 2Cl),2.02(s,3H,CH 3).HR-MS(ESI):calcd.for C18H16N6O2[M+H+]392.1471found392.1453.
Example 25
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (4-biphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (4-biphenylphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] ne]Imidazol-1-yl) -N- (4-biphenylphenyl) acetamide. TLC detection is one point, dark spots exist under an ultraviolet lamp at 254nm, and no fluorescence exists under 365 nm.1H NMR(300MHz,DMSO-d6):δ10.70(s,1H,NHCO),7.87(t,J＝8.64Hz,2H,ArH),7.70-7.63(m,6H,ArH,ArH),7.49-7.33(m,5H,ArH),7.04(s,2H,ArH),5.62(s,2H,CH 2Cl).
Example 26
2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide
Referring to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (3,4, 5-trimethoxyphenyl) acetamide to obtain a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] b]Imidazol-1-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide (compound 22). TLC detection was one point, UV lamp 254nmDark spots appear in the lower part, and no fluorescence exists at 365 nm.1H NMR(300MHz,DMSO-d6):δ10.43(s,1H,NHCO),7.87(d,J＝7.26Hz,1H,ArH),7.78(d,J＝7.47Hz,1H,ArH),7.36-7.48(m,2H,ArH),6.96(s,4H,ArH,NH 2),5.57(s,2H,CH 2Cl),3.72(s,6H,OCH 3,OCH 3),3.63(s,3H,OCH 3).HR-MS(ESI):calcd.for C18H16N6O2[M+H+]425.1573found 425.1558.
Example 27
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (benzo [ d ] [1,3] dioxol-5-yl) acetamide:
referring to the synthesis of example 1, intermediate 2 in example 1 was replaced with 2-chloro-N- (benzo [ d ]][1,3]Dioxol-5-yl) acetamide to obtain a light yellow solid compound, namely 2- (2- (4-amino-1, 2, 5-oxadiazole-3-yl) -1H-benzo [ d ]]Imidazol-1-yl) -N- (benzo [ d)][1,3]Dioxol-5-yl) acetamide (Compound 23).1H NMR(300MHz,DMSO-d6):δ10.49(s,1H,NHCO),7.84(dd,J＝7.62,15.69Hz,2H,ArH),7.47-7.36(m,2H,ArH),7.24(d,J＝1.95Hz,1H,ArH),7.02(s,2H,NH 2),6.97(dd,J＝2.07,8.40Hz,1H,ArH),6.87(d,J＝8.4Hz,1H,ArH),5.98(s,2H,OCH 2O)5.55(s,2H,CH 2Cl).
Example 28
Synthesis of 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (2, 3-dimethylphenyl) acetamide:
with reference to the synthesis method of example 1, the intermediate 2 in example 1 was replaced with 2-chloro-N- (2, 3-dimethylphenyl) acetamide to give a pale yellow solid compound, i.e., 2- (2- (4-amino-1, 2, 5-oxadiazol-3-yl) -1H-benzo [ d ] b]Imidazol-1-yl) -N- (2, 3-dimethylphenyl) acetamide (compound 24).1H NMR(300MHz,DMSO-d6):δ9.94(s,1H,NHCO),7.86(dd,J＝4.74,7.82Hz,2H,ArH),7.48(t,J＝6.90Hz,1H,ArH),7.36(t,J＝6.87Hz,1H,ArH),7.08(t,J＝3.18Hz,1H,ArH),7.01-7.04(m,4H,ArH,NH 2),5.62(s,2H,CH 2Cl),2.24(s,3H,CH 3),2.13(s,3H,CH 3).
Structural formulas of the compounds synthesized in examples 1 to 28
The following are some of the compounds of the invention tested for pharmacodynamics and the results:
determination of cholinesterase inhibitory Activity:
drugs and reagents: test compounds, AChE (e.c.3.1.1.7, Type VI-S, selected from eels), BuChE (e.c.3.1.1.8, selected from horse serum), 5' -dithiobis (2-nitrobenzoic acid) (DTNB), Acetylthiocholine (ATC) iodide, and Butyrylthiocholine (BTC) iodide were purchased from sigma; the positive control tacrine hydrochloride (9-Amino-1,2,3, 4-tetraacetidine hydrochloride) was purchased from BioTrend corporation.
The instrument comprises: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.
The experimental method comprises the following steps:
(1) preparing a buffer solution: 13.6g of potassium dihydrogen phosphate were dissolved in 1L of water, and the pH was adjusted to 8. + -. 0.1 with potassium hydroxide. The solution was stored at 4 ℃ until use.
(2) Preparing 0.01M DTNB solution: 0.396g of DTNB and 0.15g of sodium bicarbonate were dissolved in 100mL of water to prepare a 0.01M DTNB solution, which was stored at-30 ℃ for further use.
(3) Preparing 0.075M ATC and BTC solution: dissolving 0.217g ATC in 10mL water to obtain 0.075M ATC and BTC solution, and storing at-30 deg.C; 0.237g BTC was dissolved in 10mL water to make a 0.075M BTC solution, which was stored at-30 ℃ until use.
(4) Preparing AChE and BuChE solutions: dissolving 5000 units of AChE in 1mL of 1% gel solution, diluting with water to 100mL to obtain AChE solution with concentration of 5 units/mL, and storing at-30 deg.C; 5000 units of BuChE was dissolved in 1mL of 1% gel solution, and then diluted to 100mL with water to prepare a BuChE solution having a concentration of 5 units/mL, which was stored at-30 ℃ for use.
(5) Preparing a test solution: test compound was dissolved in ethanol to give a concentration of 10-3M (ethanol did not affect the test results), and then diluted with water to give concentrations of 10 -4、10-5、10-6、10-7、10-8、10-9、10-10M in water.
Before the experiment was started, all solutions were warmed to room temperature and the AChE, BuChE solution was diluted one-fold with water to make an enzyme solution with a concentration of 2.5 units/mL. Background UV absorbance was measured using blank buffer (3 mL). Adding 100 mu L of test compound solution, 100 mu L of DTNB solution and 100 mu L of enzyme solution into 3mL of buffer solution, immediately timing and simultaneously rapidly mixing the test solution after 20 mu L of ATC or BTC solution is added to trigger reaction, and measuring the ultraviolet absorbance at the wavelength of 412nm after 2 min. The blank control was measured using an equal volume of water instead of the test solution. All tests were run in parallel in triplicate. The absorbance (OD value) of the test compound at each concentration was recorded by taking the UV absorption value of the blank as 100%, and the result was obtained using GraphPad PrismTM(GraphPad Software, San Diego, Calif., USA) Software calculates the corresponding IC by non-linear regression analysis model50Values, as shown in table 1.
TABLE 1 test results of the compounds on eqBuChE
aShows the inhibition rate of the compound to the target at a concentration of 10. mu.M
The compounds in table 1 all showed good inhibitory activity against BuChE (the best compound, compound 6, showed 20nM inhibitory activity against BuChE), and no inhibitory activity against AChE (the inhibition rate at 10 μ M concentration was less than 10%), indicating that the series of compounds have very high selectivity. In the early stage of AD, 80% of ACh is hydrolyzed by AChE, BuChE has little effect, the level of AChE is reduced and the function is almost lost along with the aggravation of the disease course, and at the moment, the level and the function of BuChE are relatively improved to replace AChE to become the main metabolic enzyme of ACh. Thus, BuChE inhibitory activity is particularly important for the treatment of severe AD. In order to prevent unnecessary peripheral choline-like side effects caused by the influence of the compound on peripheral AChE, the development of a selective BuChE inhibitor has great significance. The compound has good inhibitory activity and high selectivity on BuChE, and is expected to produce good curative effect on mild and severe AD.
Morris Water maze study mouse behaviourology study
The instrument comprises: panlab SMART 3.0 behavioural video analyzer
Animals: adult male ICR mice (8-10 weeks, 20-25 grams in body weight) were purchased from the Yangzhou university medical center.
Reagent: scopolamine hydrobromide was purchased from alatin reagent (S107418, shanghai), tacrine (purity > 95%), compound 1, compound 5, compound 6, compound 7.
The experimental method comprises the following steps: the 56 mice were randomly divided into 7 groups (8 mice per group): control group, model group, tacrine group, compound 1-treated group, compound 5-treated group, compound 6-treated group, and compound 7-treated group. Tacrine, compound 1, compound 5, compound 6, compound 7 were dissolved in CMC-Na solution (0.5g CMC-Na, 100mL distilled water), respectively, and administered by gavage (15mg/kg body weight). After 30min, mice in the model group, tacrine group, compound 1 treatment group, compound 5 treatment group, compound 6 treatment group and compound 7 treatment group were injected with scopolamine (1mg/kg) intraperitoneally, and mice in the control group were injected with normal saline intraperitoneally. The cognitive function and memory of the mice were tested by the water maze. An escape platform (diameter 10cm) is fixed in a circular water pool (diameter 120cm, height 60cm), a small flag (height 5 cm) is fixed on the platform, water with height 40cm is filled in the water pool, and the water maze is formed by keeping the temperature at 25 ℃. The mice are placed on an escape platform for training on days 1-2 after taking the medicine, the platform is placed 1cm under water on days 3-5, the mice are trained, the platform is moved away on the last day (day 6), the mice are evaluated, and the time, the track and the speed of the mice reaching the position of the platform are recorded. The experimental results are shown in table 2, fig. 1, and fig. 2.
TABLE 2 time at which the mouse reached the platform
####Indicates significant difference, P value<0.0001；**Indicates significant difference, P value<0.01；***Indicates significant difference, P value<0.001；****Indicates significant difference, P value<0.0001；
And (4) analyzing results: as can be seen by combining the results in Table 2, FIG. 1 and FIG. 2, the average time of arrival at the plateau of the mice in the model group was significantly increased compared to the control group, indicating that scopolamine causes memory deficiency in the mice and that the molding was successful. Compared with the model group, the time and distance consumed by the tacrine group are obviously reduced, which indicates that the tacrine has obvious improvement on the memory and cognitive functions of the mice. And the time and distance of arrival of the mice in the compound 1 treatment group, the compound 5 treatment group, the compound 6 treatment group and the compound 7 treatment group are obviously lower than those in the model group and are lower than those in the tacrine group, which shows that the compounds 1, 5, 6 and 7 improve the memory and cognitive functions of the mice and have better effects than tacrine. In addition, as can be seen in fig. 2A-G, the trajectories of the model group mice are significantly more chaotic relative to the blank group; the disorder degree of the route passed by the mice in the tacrine group is reduced compared with that of the model group, which shows that the memory and cognitive functions of the mice in the tacrine group are improved; the trace disorder degree of the mice in the compound 1 treatment group, the compound 5 treatment group, the compound 6 treatment group and the compound 7 treatment group reaching the platform is obviously lower than that in the model group and is superior to that in the tacrine group, which shows that the compound 1, the compound 5, the compound 6 and the compound 7 have obvious memory and cognitive function improving effects on the mice and are superior to that in tacrine.
Claims (6)
1. A compound represented by the following formula or a pharmaceutically acceptable salt thereof,
2. the compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate, citrate; wherein the pharmaceutically acceptable salt of the compound has the same or better pharmacodynamic activity as the compound of claim 1.
3. A process for the preparation of a compound according to claim 1, characterized in that it comprises: 2-cyanomethyl benzimidazole as initial raw material is reacted by sodium nitrite and hydroxylamine hydrochloride to obtain 4- (1H-benzo [ d ]]Imidazol-2-yl) -1,2, 5-oxadiazol-3-amines
The arylamine with different ring systems and different substitutes respectively reacts with chloroacetyl chloride, 3-chloropropionyl chloride and 4-chloroButyryl chloride or 5-chloro valeryl chloride to form corresponding amide intermediate
Then 4- (1H-benzo [ d ]]Imidazol-2-yl) -1,2, 5-oxadiazol-3-amines
The compound of claim 1, shown as formula (I), is prepared by the following reaction route:
4. use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of alzheimer's disease associated with butyrylcholinesterase.
5. The use according to claim 4, characterized in that the medicament is prepared into a pharmaceutical preparation by taking the compound or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient or a main active ingredient and a pharmaceutically acceptable carrier; the medicinal preparation is tablets, capsules, powder, syrup, liquid, suspending agent or injection.
6. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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